Viral infection is the most important infectious disease in the world, with a global incidence of about350Million people died of viral infection. near10Years, severe acute respiratory syndrome（severe acuterespiratory syndrome，SARS）Middle East respiratory syndrome, type AH1N1Influenza virusH7N9（severe acuterespiratory syndrome coronavirus 2，SARS-CoV-2）The large-scale outbreak of such viruses has brought serious harm to human life and health. In addition, hepatitis viruses such as hepatitis A virus（hepatitis A virus，HAV）, hepatitis B virus（hepatitisB virus，HBV）（hepatitis C virus，HCV）It is an important inducer of liver fibrosis, liver cancer and other diseases[1]. herpes simplex virus（herpes simplex virus，HSV）It is also a stubborn virus that infects the host for life. It often causes herpetic skin disease, which can occur in the mouth, skin, mucosa and external genitalia, and is often accompanied by sequelae such as neuropathic pain, which brings great pain to patients. At present, there is no specific target forHSVOf therapeutic drugs and vaccines. In addition, human immunodeficiency virus（human immunodeficiemcy virus，HIV）It is still the number one killer of the immune system of patients worldwide. According to the World Health Organization,2020Years have2600Million people were diagnosed with AIDS, while in2019At the end of the year, there are3270. The prevalence of other viruses, such as Zika virus and Ebola virus, has also caused serious harm to human health. The treatment of the above viral infections is still a challenging problem facing the world:（1）There are great difficulties in the research of new antiviral drugs. Due to the wide variety and strong variability of virus families, the drug specificity is poor, which brings great difficulties to the research of new drugs; The（2）The existing drugs mainly act on the structural proteins of the virus, and the high variability of the virus has produced an obvious tendency of drug resistance; The（3）There are broad-spectrum antiviral drugs such as ribavirin that can inhibit most viruses, but its adverse reactions such as lung function degradation should not be underestimated; The（4）Although vaccines are effective drugs against viral infections, their development is difficult and the phenomenon of immune drift is becoming more and more obvious. The drug loading system of vaccines is not mature, and its stability has also become a bottleneck problem in vaccine development.
Viral diseases belong to the category of "epidemic disease" in traditional Chinese medicine. Traditional Chinese medicine has accumulated rich theoretical and practical experience in the thousands of years of struggle against plague. Traditional Chinese medicine has its unique advantages in the treatment of viral diseases. Screening antiviral drugs from traditional Chinese medicine has become a research hotspot at home and abroad[2]。
Alkaloids are important components of natural products with structural diversity, which have been reported so far60There are many kinds. According to the structure, they are mainly divided into organic amines (ephedrine, motherwort, colchicine), pyrrolidines (senectine, monocrotaline), pyridines (arecoline, lobeline), Isoquinolines (berberine), indoles (vincristine, ergonovine), anisodanes (atropine, scopolamine), imidazoles (pilocarpine), quinazolines (evergreen), purines (caffeine, theophylline), steroids (solanine, Fritillaria alkaloid), diterpenes (aconitine, delphinide) and other categories (galantamine, triptolide), see table1Alkaloids also exhibit inhibitory activity against a variety of viruses, such as influenza A virus（influenza A virus，IAV）、HBV、HCV、HSV、HIV, Zika virus, Coxsackie virus（coxsackie virus，CV）And tobacco mosaic virus（tobacco mosaic virus，TMV）Et al., as shown in Fig1Shown in.
1 resistIAVActivity and its mechanism
Influenza is a disease caused byIAVRespiratory diseases caused by infection are often accompanied by sneezing, sore throat, fever, headache, muscle fatigue and other symptoms[30]At present, the main drugs used for anti influenza virus areRNAPolymerase inhibitors (e.g., ribavirin)M2Channel blockers (such as amantadine and rimantadine), neuraminidase inhibitors (such as zanamivir and oseltamivir), and the hemagglutinin inhibitor baloxavir.
Oxymatrine（oxymatrine，OMT）It is the main active ingredient of Sophora flavescens and has many biological activities, such as antioxidant, anti-inflammatory, antiviral, etc[31],OMTIt has a significant inhibitory effect on influenza virus and its induced inflammation, and its mechanism and downregulationIAVInduced protein kinasesB（protein kinase B，PKB/Akt）, extracellular signal regulated kinase1/2（extracellular signal-regulatedkinase1/2，ERK1/2）、p38Mitogen activated protein kinase（p38 mitogen-activated protein kinase，p38 MAPK）, nuclear factor-κB（nuclear factor-κB，NF-κB）Activity, which is related to the reduction of inflammatory cytokine levels. Ephedrine, the main active ingredient in ephedra, has anti-inflammatory properties[32], antipyretic[33], analgesic and anti influenza effects[34],L-Methylephedrine（L-methylephedrine，L-MEP）、L-Ephedrine andD-Pseudoephedrine（D-pseudoephedrine，D-PEP）Can be down regulated byTollLike receptor3（Toll-like receptor 3，TLR3）, tumor necrosis factor receptor related factors3（tumor necrosis factor receptor-associated factor 3，TRAF3）3（interferon regulating factor 3，IRF3）、TLR4、TLR7, myeloid differentiation factor88（myeloid differentiation factor 88，MyD88）、TRAF6Expression to exert anti -H1N1Influenza and anti-inflammatory effects[3]（nuclear protein，NP）The highly conserved region of the virus binds to inhibit its nuclear export and oligomerization, resulting in viral ribonucleoprotein（viral ribonucleoprotein，νRNP）CompoundRepress influenza virus replication and transcription by reducing its activity[35]. harmine, harmine, and harmine（harmine，HM）[36]It's from a camel's penβ-Carboline alkaloids, with antifungalHIVandCMV[37-38]Isoactivity. Studies have proved that harmala alkaloids（total alkaloid ofpeganum harmalal，TAH）Can be suppressed byIAVPolymerase andNPIntervention due to protein activityνRNPComplex synthesis, inhibiting virusRNATranscription and replication of[39]。
Berberine was obtained from Rhizoma Coptidis、Isoquinoline alkaloids isolated from heat clearing and detoxifying traditional Chinese medicines such as Phellodendron amurense are also effective forIAVIt has a strong inhibitory effect, and its mechanism and mediationMAPK、ERKAnd other signaling pathways[12],MAPKThe signaling pathway is closely related to viral ribonucleoprotein transport, whileERK1Pathways areIAV RNPAn important channel for the nuclear export of the complex, both of which are involved inIAVReplication and transcription of[40]Berberine can also down regulate tumor necrosis factor-α（tumor necrosis factor-α，TNF-α）E2（prostaglandin E2，PGE2）To inhibit the maturation and trafficking of viral proteins, thereby inhibiting viral replication and expansion[13]。
In summary, it has anti -IAVThe chemical structure of the active alkaloid is shown in Fig2, its anti -IAVSee Fig3. alkaloid anti -IAVMainly through regulationMAPK/ERKsignaling pathway、 adjustTLROf related genes in the signaling pathwaymRNAExpressionνRNPComplex synthesis to affect viral cell replication, transcription, protein synthesis, play an anti influenza A virus role.
2 Anti hepatitis virus activity and its mechanism
Viral hepatitis is caused byHAV、HBV、HCVLiver inflammation caused by isophagic viruses is the culprit of irreversible liver lesions such as liver fibrosis and liver cancer worldwide. Among them, hepatitis B is caused byHBVAn infectious disease caused by infection,HBVInfection of hepatocytes can cause inflammatory reaction and secondary injury of hepatocytes. WithHBV,HCVBelongs to positive chainRNAFlaviviridae viruses,HCVAfter infection, it can progress to cirrhosis and hepatocellular carcinoma, with concealed onset and slow development.
It is now clear that,OMTrightHBVIt has strong inhibitory effect and has been used in the clinical treatment of hepatitis B in China[41-43],OMTCan be activated byTLR9signal transduction pathway [44]Mediates the production of antiviral cytokines and downregulates interleukins-4（interleukin 4，IL-4）、IL-10And other inflammatory factorsHBV[45]。OMTCan also activate innate immunity to induceCD4+ TIn cellsγ（interferon-γ，IFN-γ）To inhibit the production ofHBVcopy[46-47]. in addition,OMTBut also by downregulating heat stress homologous proteins（heat shock cognate 70，Hsc70）To inhibit the expression ofHBVReplication of[48-49]。Sophoridine in Sophora flavescens can inhibitp38 MAPK、TRAF6、ERK1, nucleotide binding oligomerization domain like receptor protein10（NOD-like receptor protein 10，NLRP10）And cysteine containing aspartate proteolytic enzyme, respectively..the enzyme of the protein hydrolysis of aspartate and cysteine containing protein of aspartate and cysteine of aspartate and cysteine containing protein of aspartate and cysteine of aspartate and cysteine of aspartate and aspartate of aspartate and cysteine-1（cysteinyl aspartate specificproteinase-1，Caspase-1）mRNAExpression, downregulationTRAF6 mRNAAnd so onHBVProliferation. Stephanine can also inhibitHsc70Active antiHBVRole.
Tetradesoxyphylline（dehydrocheilanthifoline，DHCH）It is a quaternary ammonium alkaloid extracted from Rhizoma Coptidis.DHCHCan be suppressed byHBV DNAAnd covalently closed ringsDNA（covalently closed circle DNA，cccDNA）Level and inhibitHBVactivity[50-51],DHCHIt can also effectively inhibit human liver cancerHepG2.2.15HBsAg in cells（hepatitis B surfaceantigen，HBsAg）And hepatitis BeAntigen（hepatitis Be antigen，HBeAg）Expression to exert anti -HBVRole. In addition, berberine also has significant anti -HCVRole. Berberine can interact withHCV E2Glycoprotein interactions, targeting virusesE2Glycoproteins to inhibitHCVcopy[15,52]Sophorine is a natural alkaloid isolated from Sophora alopecuroides[53]. Sophora alopecuroides can be intervened byHCVTo block the process of membrane fusion with host cellsHCVCell penetration, while inhibitingHCVAdaptive mutation of[54]。
To sum up,The chemical structure of alkaloids with anti hepatitis virus activity is shown in Fig4，hisAnti hepatitis virusSee Fig5Alkaloids against hepatitis virus mainly through regulationTollLike receptor signaling pathway, interference with virus transmembrane penetration, inhibition of viral proteinsHBeAgandHBsAgActivity, downregulation of viruscccDNALevel to interfere with virus replication and amplification, so as to play an anti hepatitis virus role.
3 resistHSVActivity and its mechanism
herpes simplex virus1Type（herpes simplex virus-1，HSV-1）andHSV-2Is a highly prevalent pathogen worldwide, and twoAre closely related.HSV-1It is a complex envelopedsDNAViruses, which have evolved to replicate in human neurons and epithelial cells[55]。HSV-2Is the main cause of genital ulcer[56], is an important driver of the HIV epidemic.
Alkaloids have also been reported to be effective againstHSVExhibited inhibitory effects.HMBy blocking host cytokines-1（host cell factor-1，HCF-1）And lysine specific histone demethylases1（lysine specific demethylase 1，LSD1）Interaction between them to inhibit viral protein expression[57]，HCF-1Is the most important host cytokine that determines the successful infection of herpes simplex virus, is the activation ofHSVCore organization of immediate early genes.Bagetc.[58]reportHMAlso by blocking immediate early genes and proteins of infected cells0（infected cell protein 0，ICP0）The binding of promoter inhibits the transcriptional expression of early viral protein.HMIt has also been reported to inhibit by downregulating early protein expressionHSVLate proteins such asICP5Expression of[59]。HMIt can also down regulate infected host cellsNF-κBandMAPKPathway to inhibitHSVcopy[17,60-61]。
Salimetc.[62]Through chemical structure modification research, it was found that,β-Effect of methylation modification in the structure of carboline alkaloid on its anti -HSVActivity has a great impact. β-Carboline alkaloids such as6-Methoxy HarmanAlkali9-Methyl Harman base and9-Methyl norharmanine onHSV-1 ICP0It has a better inhibitory effect. HSVInhibition, its mechanism and interventionHSVInducedNF-κBActivate related[16-17]In addition, berberine can also inhibitHSVInducedJun-（c-Jun N-terminal kinase，JNK）Phosphorylation[17], and toJNKDownstream transcriptional activator protein1（activator protein-1，AP-1）It has inhibitory effect.
In summary, it has anti -HSVThe chemical structure of the active alkaloid is shown in Fig6，Its antiHSVSee Fig7It has been shown in the literature that alkaloids directly or indirectly resistHSVRole, mainly related to regulationJNK/MAPKPathway, inhibitionHSVExpression and interference of immediate early genes, early proteins and late proteinsHSVOfDNAReplication is related to pathways such as reverse transcriptase.
4 resistHIVActivity and its mechanism
AIDS is caused byHIVInfectious diseases caused by.HIVThe virus mainly attacks theCD4+ TLymphocytes, leading to the decline or even collapse of immune function. Current antiHIVThe main drugs are viral reverse transcriptase, fusion enzyme and protease inhibitors.
Alkaloids were also found in someHIVCompounds exhibiting activity. Camptothecin was obtained from Camptotheca acuminataCamptotheca acuminata Decne.Quinoline alkaloids isolated from. HIVIt has certain inhibitory effect. The structurally modified camptothecin derivatives such as9-Nitrocamptothecin7-Hydroxymethyl camptothecin and others have strongerHIVInhibitory effect[63-64], its antiviral activity is mainly through the protection of cytopathic effects and inhibition ofHIV-1 p24Protein production plays a role. The study also found that10-Hydroxycamptothecin has weak antiviral activityCamptothecin modified with other hydroxyl groups. Aloperine has also been reported to have anti -HIVeffect[53,65]. aloperine can inhibitHIV-1andC-CChemokine co receptor5（C-C chemokine coreceptors 5，CCR5）、C-X-CChemokine co receptor4（C-X-C chemokine coreceptors 4，CXCR4）To block theHIV-1To controlHIV-1Infection. Host cell surfaceCCR5andCXCR4Can be compared withHIV gp120Protein binding, causinggp120Conformational change, startHIV-1Fuse with the target cell membrane to infect the host cellHIVvirus[66]Violadine and norisopordine were isolated from the leaves of Aconitum carmichaeli2Alkaloids,Ravanellietc.[67]Research has proved that this2All alkaloids can produce antiHIVRole.
To sum up,With anti -HIVThe chemical structure of the active alkaloid is shown in Fig8，Its antiHIVSee Fig9The alkaloids represented by camptothecin, aloperine, violidine, norisopordine, etc. have anti -HIVAction, the mechanism of which is mainly through blockingHIVSurface glycoproteins such asgp120And host cell receptors such asCCR5、CXCR4Etc. to produce anti -HIVRole. Also by inhibitingHIVOf reverse transcriptase activity to exert antiviral effects.
5 other
In addition to the above viruses, alkaloids are also effective againstSARS, dengue virus（dengue virus，DENV）、CVB3, human cytomegalovirus（human cytomegalo virus，HCMV）And other viruses have inhibitory effects. Quinoline alkaloid chloroquine onSARS-CoV-2Showed a good inhibitory effect, and by reducing theTNF-α、IL-6And other inflammatory factors to alleviate the inflammatory injury in the middle and late stages of infection[68]Lycopene is a steroidal alkaloid isolated from tomato leaves and peel,Diosa-Toroetc.[69]In vitro studies have demonstrated that lycopene has a significant effect onDENVShowed good inhibitory activity.
The same alkaloid can also show biological activity against a variety of viruses. asOMTrightHBV、IAVandCVB3.OMTrightCVB3Induced myocarditis in mice has a protective effect, and its mechanism is related to the reduction ofCVB3Non coding regions andTNF-αThe expression of[70]Emetine is an isoquinoline alkaloid isolated from the roots of Brazilian soilHCMVAnd Zika virus have inhibitory effects. Among them, emetine inhibitedHCMVOf replication occurs after virus entryDNABefore copying.Mukhopadhyayetc.[71]It was found that emetine had a significant effect onHCMVThe inhibition of is dependent on ribosomal proteinsS14（ribosomal protein S14，RPS14）With mouse derived doublets2（murine double minute 2，MDM2）The combination of,MDM2-RPS14The interaction ofRPS14Of ubiquitination and degradation, makingHCMVInfection inducedMDM2-p53andMDM2-IE2Disruption of the interaction while significantly reducingHCMVProtein expression to inhibit viral translation. In addition, emetine also binds Zika virusRNAThe active site of polymerase, which effectively inhibitsRNAPolymerase activity. At the same time, emetine can also block lysosomal autophagy of host cells and enhance the clearance of Zika virus[72]Berberine can also act through a similar pathwayEV71。EV71Replication can be achieved by disrupting the fusion of autophagosomes and lysosomes[73], making itselfRNAAnd proteins are not degraded. Berberine can increaseAktPhosphorylate and reduceJNKPhosphorylation to inhibitEV71Induced autophagy thereby reducing virusRNAAnd protein synthesis[14]In addition, berberine can also down regulateERKSignaling pathway inhibitionEV71.
Lycorine is a natural isoquinoline alkaloid extracted from lycoris radiata, a plant of Lycoris radiata family. It has many biological activities such as antiviral, antibacterial, antiparasitic and anti-inflammatory[74]Lycorine can inhibitRNADependencyRNAPolymerase（RNA-dependent RNA polymerase，RdRp）Activity to inhibit Zika virus replication. In addition, lycorine can also inhibit the proliferation ofHsc70To inhibit the expression ofHCVReplication of[75-76]It can be seen that lycorine is an active compound with broad-spectrum antiviral potential.
6 Conclusion and Prospect
Alkaloids have inhibitory effects on a variety of viruses, and their mechanisms of action also show diversity. They can not only directly act on the virus itself, but also regulate the internal pathways of host cells to produce antiviral effects. aboutIAV, alkaloids can directly inhibitIAVReplication and blocking of virusRNANuclear protein to directly kill the virus. Alkaloids can also exert antiviral activity by regulating host factors and alleviate the virus inducedCytopathic effectThe mechanism is mainly through regulationMAPK/ERKsignaling pathway、TLRsignaling pathway、νRNPComplex synthesis and other pathways to affect viral cell replication, transcription and protein synthesis, thereby exerting anti -IAVThe role of. The antiviral activity of alkaloids is mainly through inducing antiviral factors and activating innate immunity. Its mechanism and regulationTollLike receptor signaling pathwayHsc70signaling pathway、TRAF6Pathway, etc. In addition, alkaloids can also regulateJNK、MAPKs、NF-κBWait for signaling pathway to suppressHSVThe expression of viral proteinsHSVVirus replication. aboutHIV, while alkaloids mainly targetHIV p24Antigen to block the entry of virus into host cells and inhibit the binding of virus to specific receptors of host to exert antiHIVActivity. Alkaloids can also inhibit Zika virus, enterovirusHCMVas well asCVBAnd other viruses show resistance, and its mechanism is mainly related to the regulationJNK、AktandMAPKAnd other antiviral cytokines to inhibit virus replication and block virusRNAIt is related to the synthesis of viral proteins, the regulation of autophagy in host cells, and the blockade of viral protein synthesis.
Alkaloids have a large number and a wide variety, and antiviral activity is only a small part of their pharmacological activity. OMTIn addition to the antiviral effects of common alkaloids such as dendrobine, berberine, harmaline, and lycorine, there are many alkaloids whose activities have not been explored yet. According to the current literature, the antiviral effects of alkaloids are mainly reflected in the following aspects:（1）It directly acts on viral proteins to inhibit virus penetration, transcription and replication. IAVNucleoproteinHSVOfICP0Protein et al; The（2）Regulating host immunity or activating antiviral factors, alkaloids can enhance intracellularDNAorRNAThe receptor recognizes the virus and activates antiviral factors, such asIRF3, interferon, etc., while also inhibiting antiviral negative regulators such asHsc70Et al; The（3）Mediate the interaction between the virus and host cells, such as enhancing the autophagy of host cells to clear the virus, inhibiting the virus induced inflammatory response of host cells, and inhibiting the binding of host cell surface receptors and virus surface antigens.
In recent years, it has become a hot spot in antiviral research by mediating endogenous antiviral immunity and the interaction between host cells and viruses. this2The three ways of antiviral mode has unique advantages in dealing with virus resistance, virus clearance, and unknown sudden virus infection. In the field of antiviral drug research, the research direction has also gradually shifted from finding viral inhibitors targeted by viral enzymes to finding antiviral targets from the interaction between natural immunity, host cells and viruses, providing a new idea for the research and development of alkaloid antiviral compounds.
Conflict of interest
References (omitted)
Come Source: Wang Hong, Liu Yue, Liang Yu Yang, Rong Shan Cai, Ying Shu Xu, Yong AI Xiong. Research progress on antiviral activity and mechanism of alkaloids [J] . Chinese herbal medicine, 2022, 53 (9): 2839-2850